Magnetically-driven biodegradable gene delivery nanoparticles formulated with surface-attached polycationic complex

Abstract

A particle including a matrix-forming agent and a polyelectrolyte-amphiphilic agent adduct wherein the polyelectrolyte-amphiphilic agent adduct is in physical communication with the matrix-forming agent. The particle further includes a coated magnetic field-responsive agent and a biomaterial. Methods of making the particle are provided. Also provided are methods of delivery of the biomaterial to a target cell or a target tissue including administering the particle having the matrix-forming agent, polyelectrolyte-amphiphilic agent adduct, the coated magnetic field-responsive agent and the biomaterial; providing a magnetic device associated with the target cell or the target tissue; applying a magnetic force to the particle; and guiding the particle toward the magnetic device by the magnetic force.

1 - 53 . (canceled) 
     
     
         54 . A particle comprising:
 a matrix-forming agent; and   a polyelectrolyte-amphiphilic agent complex formed by an ionic association of a polyelectrolyte with a first amphiphilic agent and having a C 4 -C 24  hydrocarbon chain, wherein the polyelectrolyte-amphiphilic agent complex is in physical communication with the matrix-forming agent.   
     
     
         55 . The particle of  claim 54 , wherein the matrix-forming polymer is selected from the group consisting of poly(ester), poly(urethane), poly(alkylcyanoacrylate), polyanhydride, polyethylenevinyl acetate, poly(lactone), poly(styrene), poly(amide), poly(acrylonitrile), poly(acrylate), poly(methacrylate), poly(orthoester), poly(ether-ester), poly(tetrafluoroethylene), mixtures thereof and copolymers of corresponding monomers. 
     
     
         56 . The particle of  claim 55 , wherein the poly(ester) is a member selected from the group consisting of poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(ε-caprolactone), poly(dioxanone), poly(hydroxybutyrate), and poly(ethylene terephthalate). 
     
     
         57 . The particle of  claim 54 , wherein the polyelectrolyte-amphiphilic agent complex is poly(ethyleneimine) carboxylate. 
     
     
         58 . The particle of  claim 54 , wherein the polyelectrolyte is a member selected from the group consisting of poly(ethyleneimine), poly(allylamine), poly(lysine), poly(arginine), poly(spermine), poly(spermidine) and derivatives thereof. 
     
     
         59 . The particle of  claim 54 , wherein the first amphiphilic agent is a member selected from the group consisting of fatty acids, lipids and salts thereof. 
     
     
         60 . The particle of  claim 59 , wherein the first amphiphilic agent is a C 12 -C 24  carboxylic acid. 
     
     
         61 . The particle of  claim 60 , wherein the first amphiphilic agent is oleic acid. 
     
     
         62 . The particle of  claim 54 , further comprising a biomaterial in communication with at least one of the polyelectrolyte-amphiphilic agent complex or the matrix-forming agent, wherein the particle is free of the magnetic field-responsive agent. 
     
     
         63 . A magnetic particle, the magnetic particle comprising:
 a matrix-forming polymer; and   a coated magnetic field-responsive agent comprising a magnetic field-responsive agent and an amphiphilic agent, wherein the coated magnetic field-responsive agent is in communication with the matrix-forming polymer, provided that the magnetic particle is free of a polyelectrolyte.   
     
     
         64 . The magnetic particle of  claim 63 , further comprising a biomaterial in communication with the matrix-forming polymer. 
     
     
         65 . A method of making the particle of  claim 54 , the method comprising:
 providing the matrix-forming agent;
 providing a polyelectrolyte; 
 providing a first amphiphilic agent; 
   providing a first medium and a second medium;
 optionally providing a stabilizer; 
 mixing at least the matrix-forming agent, the first medium, and the second medium and optionally the polyelectrolyte, the first amphiphilic agent, and/or the stabilizer to give a first mixture; 
   emulsifying the first mixture to give a first emulsion; and   removing the first medium and thereby forming the particle, on a condition that the polyelectrolyte, the first amphiphilic agent, and the stabilizer are provided to at least one of the first medium, the second medium, the first mixture, the first emulsion, or the particle such that the polyelectrolyte and the first amphiphilic agent form the polyelectrolyte-amphiphilic agent complex.   
     
     
         66 . The method of  claim 65 , wherein the polyelectrolyte, the first amphiphilic agent, and optionally the stabilizer are combined with the matrix-forming agent before mixing with the first medium or the second medium. 
     
     
         67 . The method of  claim 65 , wherein the first amphiphilic agent comprises a polar chemical group selected from at least one of a carboxylate group, a phosphonate group, a bisphosphonate group, a phosphate group, a sulfonate group, or a sulfate group. 
     
     
         68 . The method of  claim 65 , wherein the first medium comprises an organic solvent. 
     
     
         69 . The method of  claim 68 , wherein the first medium comprises the organic solvent selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran, acetone, ethanol, hexane, heptane, methylethylketone, propylene carbonate, ethyl acetate, acetylacetone, acetic anhydride, dimethylsulfoxide, dimethylformamide, acetonitrile and mixtures thereof. 
     
     
         70 . The method of  claim 68 , wherein the organic solvent is provided as a ratio of at least two different organic solvents wherein the ratio influences a size of the particle. 
     
     
         71 . The method of  claim 70 , wherein the least two different organic solvents are tetrahydrofuran and chloroform provided at the ratio of about 0.1 to about 10 and the particle's diameter is about 370 nm to about 153 nm. 
     
     
         72 . The method of  claim 65 , wherein the second medium is a member selected from the group consisting of water, alcohols, and liquid hydrocarbons. 
     
     
         73 . The method of  claim 65 , further comprising providing a biomaterial. 
     
     
         74 . The method of  claim 73 , wherein the biomaterial is provided to at least one of the first mixture, the first emulsion and/or the particle. 
     
     
         75 . The method of  claim 65 , further comprising providing a coated magnetic field-responsive agent to at least one of the first medium, the second medium, and/or the first mixture. 
     
     
         76 . The method of  claim 75 , wherein the coated magnetic field-responsive agent is dispersed in the first medium and mixed with the matrix-forming agent, the polyelectrolyte, the first amphiphilic agent, and the stabilizer prior to mixing with the second medium. 
     
     
         77 . The method of  claim 75 , wherein the coated magnetic field-responsive agent is provided by combining a magnetic field-responsive agent and a second amphiphilic agent in a presence of the first medium, the second medium, or the first mixture. 
     
     
         78 . The method of  claim 77 , wherein at least one of the first amphiphilic agent or the second amphiphilic agent comprises a polar chemical group selected from at least one of a carboxylate group, a phosphonate group, a bisphosphonate group, a phosphate group, a sulfonate group, or a sulfate group. 
     
     
         79 . The method of  claim 77 , further comprising providing a biomaterial. 
     
     
         80 . The method of  claim 79 , wherein the biomaterial is provided to at least one of the first mixture, the first emulsion and/or the particle. 
     
     
         81 . The method of  claim 80 , wherein the biomaterial is provided to the particle, and wherein the biomaterial is in communication with the polyelectrolyte-first amphiphilic agent complex, provided that the polyelectrolyte, the first amphiphilic agent, and the stabilizer are combined with the matrix-forming agent before mixing with the first medium. 
     
     
         82 . A method of making the magnetic particle of  claim 63 , the method comprising:
 providing the matrix-forming polymer;   providing the coated magnetic field-responsive agent;   providing a first medium and a second medium;   optionally providing a stabilizer;   mixing at least the matrix-forming polymer, the first medium, and the second medium to give a second mixture;   emulsifying the second mixture to give a second emulsion; and   removing the first medium and thereby forming the particle, on a condition that the coated magnetic field-responsive agent and optionally the stabilizer are provided to at least one of the first medium, the second medium, or the second mixture.   
     
     
         83 . The method of  claim 82 , wherein the coated magnetic field-responsive agent is provided by combining the magnetic field-responsive agent and the second amphiphilic agent in a presence of the first medium, the second medium, or the second mixture. 
     
     
         84 . The method of  claim 82 , further comprising providing a biomaterial. 
     
     
         85 . The method of  claim 84 , wherein the biomaterial is provided to at least one of the second mixture, the second emulsion or the magnetic particle. 
     
     
         86 . A method of making a particle, the method comprising:
 providing a first medium and a second medium;   providing a coated magnetic field-responsive agent;   optionally providing a stabilizer;   providing a composition comprising a matrix-forming agent, a polyelectrolyte, a first amphiphilic agent and optionally the stabilizer;   dispersing the coated magnetic field-responsive agent in the first medium to form a dispersion;   mixing the composition with the dispersion;   adding the second medium to the composition and the dispersion to form a first mixture;   emulsifying the first mixture to give a first emulsion; and   removing the first medium and thereby forming the particle.   
     
     
         87 . A particle made by the method of  claim 86 . 
     
     
         88 . The particle of  claim 87 , further comprising a biomaterial. 
     
     
         89 . A method of delivery of a biomaterial to a target cell or a target tissue, the method comprising:
 administering a magnetic particle comprising (i) a matrix-forming polymer; (ii) a coated magnetic field-responsive agent comprising a magnetic field-responsive agent and a second amphiphilic agent, wherein the coated magnetic field-responsive agent is in communication with the matrix-forming polymer, provided that the magnetic particle is free of a polyelectrolyte; and (iii) the biomaterial in communication with the matrix-forming polymer;   optionally providing a magnetic device associated with the target cell or the target tissue;   applying a magnetic force to the particle; and   guiding the particle by the magnetic force and thereby delivering the biomaterial to the target cell or the target tissue.   
     
     
         90 . A method of delivery of a biomaterial to a cell or a tissue, the method comprising:
 administering a particle comprising (i) a matrix-forming agent; (ii) a polyelectrolyte-amphiphilic agent complex wherein the polyelectrolyte-amphiphilic agent complex is in physical communication with the matrix-forming agent; and (iii) a biomaterial in communication with at least one of the polyelectrolyte-amphiphilic agent complex or the matrix-forming agent, wherein the particle is free of the magnetic field-responsive agent; and   delivering the biomaterial to the cell or tissue using the particle as a carrier, wherein the cell is optionally contacted with a transfection agent prior to said delivering.